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Oncogenic kinase signalling

Abstract

Protein-tyrosine kinases (PTKs) are important regulators of intracellular signal-transduction pathways mediating development and multicellular communication in metazoans. Their activity is normally tightly controlled and regulated. Perturbation of PTK signalling by mutations and other genetic alterations results in deregulated kinase activity and malignant transformation. The lipid kinase phosphoinositide 3-OH kinase (PI(3)K) and some of its downstream targets, such as the protein-serine/threonine kinases Akt and p70 S6 kinase (p70S6K), are crucial effectors in oncogenic PTK signalling. This review emphasizes how oncogenic conversion of protein kinases results from perturbation of the normal autoinhibitory constraints on kinase activity and provides an update on our knowledge about the role of deregulated PI(3)K/Akt and mammalian target of rapamycin/p70S6K signalling in human malignancies.

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Figure 1: Human receptor protein-tyrosine kinases.
Figure 2: Human cytoplasmic protein-tyrosine kinases.
Figure 3: Protein kinase activation mechanisms.
Figure 4: RPTK-induced PI(3)K signalling through PDK-1 and Akt.

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Acknowledgements

We apologize to all colleagues, including those instrumental in generating the large amount of data compiled in Table 1, whose papers were not cited owing to space limitations. We thank M. R. Stratton and G. Pao for providing inspiration for Table 1, and J. Leverson for critical comments and suggestions. P.B.-J. is a Special Fellow of the Leukemia and Lymphoma Society of America and T.H. is a Frank and Else Schilling American Cancer Society Professor.

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Note added in proof. Initial results showing the efficacy and safety of STI571 for treating chronic myeloid leukaemia and Kit-positive gastrointestinal stromal tumours have just been published91,92,93.

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Blume-Jensen, P., Hunter, T. Oncogenic kinase signalling. Nature 411, 355–365 (2001). https://doi.org/10.1038/35077225

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